PROJECT SUMMARY/ABSTRACT: Biomarkers of Cognitive Decline in Parkinson's Disease While patients with Lewy body disorders (LBD) share the core feature of deposition of misfolded alpha-synuclein (aSyn) into neuropathological inclusions, they exhibit pronounced heterogeneity in both initial clinical phenomenology, as well as in trajectory of outcomes. Specifically, among human patients with aSyn inclusions in neurons (or neuronal synucleinopathy), some manifest predominantly with cognitive symptoms and dementia from disease onset ? resulting in a clinical diagnosis of dementia with Lewy bodies (DLB). Others manifest predominantly with motor symptoms ? resulting in a clinical diagnosis of Parkinson?s disease (PD). Among PD patients, most subsequently develop significant cognitive decline and eventual dementia (PD with dementia, or PDD), while others do not, and the time course to PDD varies widely. The reasons for these differences in phenomenology among synucleinopathy patients are not well understood. This project aims to define endophenotypes within the LBD spectrum using objectively-measured biomarker characteristics, developing predictors of cognitive decline in PD and comparing these molecular signals to those found in DLB and Alzheimer?s disease (AD) patients. We use both unbiased screening approaches and hypothesis- driven approaches to develop genetic and biochemical biomarkers in three Aims: Specific Aim 1: Develop biochemical biomarkers of differential PD cognitive progression. Through unbiased screening of >1000 plasma proteins in >300 PD patients from multiple cohorts, we have derived a candidate list of 10 plasma proteins that predict future cognitive decline. We will assay these markers in >1000 additional PD subjects, developing multi-protein classifier panels for accurate prediction of cognitive trajectory. We will characterize these proteins in comparator groups of DLB and AD patients, as well as neurologically- normal controls. Specific Aim 2: Investigate causal influences on cognitive trajectory among LBD patients using Mendelian randomization. We will use Mendelian randomization (MR) to test the hypotheses that candidate biochemical biomarkers and AD-related disease processes causally influence cognitive trajectory in LBD. To do this, we will use as instrumental variables for MR single nucleotide polymorphisms (SNPs) nominated from (1) their relationships with protein levels of candidate biochemical biomarkers or (2) their genome-wide association with AD risk. These SNPs may then be developed as genetic biomarkers predicting cognitive trajectory in LBD. Specific Aim 3: Determine whether biochemical and genetic biomarkers predictive of cognitive decline differ for PD with vs. without GBA mutations. We propose to use a unique resource in development at the University of Pennsylvania ? the Molecular Integration in Neurological Disease (MIND) Initiative ? to compare biochemical and genetic biomarkers predictive of cognitive decline in PD with vs. without GBA mutations.